Substituted n-1,2-diphenylethyl fatty amides as cholesteremics

ABSTRACT

YL)   R-CO-NH-CH(-CH2-,R3-,R4-BENZENETRIYL)-(R1-,R2-BENZENETRI-   NOVEL AMIDE COMPOUNDS HAVING ANTIATHEROSCLEROSIS ACTIONS WHICH ARE REPRESENTED BY THE FORMULA: WHEREIN R REPRESENTS A C15-C25, STRAIGHT, CHAIN OR BRANCHED-CHAIN, NATURAL OR SYNTHETIC SATURATED OR UNSATURATE ALIPHATIC GROUP HAVING OR NOT HAVING HYDROXYL GROUP; R1, R2, R3 AND R4 REPRESENT INDIVIDUALLY A HYDROGEN ATOM, A LOWER ALKYL GROUP, A LOWER ALKOXY GROUP OR A HALOGEN ATOM BUT CANNOT BE HYDROGEN ATOMS AT THE SAME TIME. THE ABOVE-MENTIONED AMIDE COMPOUNDS CAN BE USED AS DRUGS. THEY CAN BE USED BY ADDING THEM TO FOOD-STUFF ADDITIVES SUCH AS BUTTER AND THE LIKE FOR PREVENTING THE DEPOSITION OF CHOLESTEROL ONTO THE WALLS OF BLOOD VESSELS.

1971 YASUSHI NAKAMURA 3,597,455

SUBSTITUTED N'l,Z-DIPHENYLETHYL FATTY AMIDES A5 CHOLESTEREMICS FiledApril as, 1969 2 Sheets-Sheet 1 25 3 1 0 7 a 9 /0 /3 /w l I I I I I I II 07/-(3/C0/VHCH CH2 Q 20 Gal,

0 l I 1 I l 4 1 l l n l x 1 l 4 2800 2000 #900 /500 /200 /000 000 5000'- l l 1 l 1 l l 4000 2800 2000 /800 A500 I200 /000 M M/ M ATTORNEYIUnited Sta es Patent Int. Cl. char 7/00 US. Cl. 260-404 42 ClaimsABSTRACT OF THE DISCLOSURE Novel amide compounds havingantiatherosclerosis actions which are represented by the formula:

1 R C ONH-CH- I R2 I Rs cs wherein R represents a (E -C2 Straight chainor branched-chain, natural or synthetic, saturated or unsaturatedaliphatic group having or not having hydroxyl group; R R R and Rrepresent individually a hydrogen atom, a lower alkyl group, a loweralkoxy group or a halogen atom but cannot be hydrogen atoms at the sametime.

The above-mentioned amide compounds can be used as drugs. They can beused by adding them to food-stuff wherein R represents a C C'25,straight chain or branched-chain, natural or synthetic, saturated orunsaturated aliphatic group having or not having hydroxyl group; R R Rand R represent individually a hydrogen atom, a lower alkyl group, alower alkoxy group or a halogen atom but cannot be hydrogen atoms at thesame time.

An object of the present invention is to provide novel amide compounds,which are effective for prevention of hypercholesterolemia andatherosclerosis.

Another object is to provide a process for preparing said novel amidecompounds.

A further object is to provide pharmaceutical compositions containingsaid novel amide compounds as active ingredients.

Fatty acid amide derivatives involved in the present invention haveexcellent cholesterol-lowering actions and preventing actions ofatherosclerosis and, as the result of toxicity tests carried out for thepast several years, it has been found that they have no undesirableacute and chronic toxicity.

The present compounds are used at a dosage of 0.1 g.- 10 g./ day forhuman beings. They are used with or without admixing with suitablecarriers. It is preferable to apply in the form of capsule, tablet,powder etc.

In the accompanying drawings, FIGS, 1 to 4 show infrared absorptionspectra of several amide compounds obtained in accordance with thepresent invention.

Figure:

(Compound of Example 2.)

Q CH2 (Compound of Example 14.)

l CHz-Q-O on:

(Compound 01 Example 15.)

(Compound of Example 3.)

i GHQ additives such as butter and the like for preventing the The fattyacids and reactive derivatives thereof which deposition of cholesterolonto the walls of blood vessels. are involved in the present inventionare saturated fatty This application is a continuation-in-part of US.Ser. No. 794,038 filed on Jan. 27, 1969 now abandoned.

This invention relates to novel amide compounds represented by theformula shown below, to a process for the preparation and toapplications thereof.

acids such as palmitic, stearic, isostearic, arachidic, behenic,lignoceric, pentacosanoic and hexacosanoic acids; and unsaturated fattyacids such as palmitoleic, zoomaric, oleic, petroselinic, elaidic,vaccenic, 'gadoleic, erucic, brassidic, selacholeic, linoleic,linoelaidic, ricinoleic, eleostearic, linolenic, parinaric,eicosatetraenoic, arachidom'c, eicosapentaenoic and docosapentanoicacids. These may Patented Aug. 3, 1971 be used either individually or inadmixture. Fatty acids of the natural oils shown below, preferablyliquid acids obtained from the said natural oils, reactive derivativesthereof and glycerides themselves may also be used. The natural oilsinclude hemp-seed oil, linseed oil, perilla oil, oiticica oil, kaya oil,walnut oil, poppy-seed oil, safliower oil, watermelon-seed oil, soybeanoil, sunflower oil, rice bran oil, pumpkin-seed oil, kaoliang oil,sesame oil, corn oil, rape oil, cottonseed oil, olive oil, cashew oil,tsubaki oil, ergot oil, castor oil, peanut oil, palm oil, palm kerneloil, coconut oil, beef tallow, lard, bone oil, horse fat, locust oil,chrysalis oil, shark oil, cuttlefish oil, sardine oil, mackerel oil,saury oil, herring oil, saurel oil, cod oil, trout oil, grey mullet oil,tunny oil, menuke oil, menhaden oil, eel oil, flatfish oil, whale oil,liver oil and residual oil. Further, the reactive derivatives includefatty acid halides, lower alkyl esters of fatty acids, and mixed acidanhydrides thereof with esters of chloroformic acid.

The amines employed in the present invention are benzylbenzylamines inwhich at least one phenyl group has been substituted by a lower alkylgroup such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl ort-butyl group; a lower alkoxy group such as a methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy or t-butoxy group; or a halogenatom such as a fluorine, chlorine, bromine or iodine atom, eitherindependently or in admixture. These amine compounds can be synthesizedby a process disclosed in, for example, Organic Synthesis, Bound Number,vol. II, page 318 or 503, or Journal of American Chemical Society, vol.68, page 1866 (1946).

Further, the above amine may be resolved into optical isomers accordingto a method described in, for example, Journal fiir 'Praktische Che-mic,vol. 101, page 296 (1921), whereby desired optically active amines canbe obtained in high yields. These optically active amines are alsousable for preparation of the present amide derivatives.

The amide derivatives of the present invention are prepared by reactinga fatty acid represented either by the formula RCOA wherein R is asmentioned previously; and A is a hydroxyl group, a lower alkoxy group ora halogen atom, or by the formula RCO RsCO (III) wherein R is asmentioned previously; and R is a lower alkoxy group, or a reactivederivative thereof or a glyceride containing said fatty acid, with abenzylbenzylamine derivative represented by the general formula R4 (IV)wherein R R R and R are as mentioned previously. Modes of practice ofthe above reaction are explained below.

(1 DI-SUBSTITUTED CARBODIIMIDE METHOD In this method, a di-substitutedcarbodiimide is used as a dehydrating agent for said acid and amine. Asthe (ii-substituted carbodiimide, there may be useddiisopropylcarbodiimide, dicyclohexylcarbodiimide, diphenylcarbodiimideor the like. Of these, however, dicyclohexylcarbodiimide is mostcommonly employed.

According to this method, said fatty acid, di-substituted carbodiimideand amine are individually dissolved in an inert solvent. Subsequently,the three solutions are mixed together under stirring at roomtemperature or below, and the mixed solution is allowed to stand at roomtemperature for several hours to several ten hours, whereby the reactionis complete.

In the above reaction, (ii-substituted urea is formed from saiddi-substituted carbodiimide. When recovered and dehydrated, thedi-substituted urea can be regenerated to, and reused as, thedi-substituted carbodiimide. Therefore, it can be said that this methodis quite economical.

(2) THERMAL DEHYDRATION METHOD According to this method, said fatty acidis charged with an equimolar or excess amount of the amine and themixture and condensed by dehydration. The reaction mixture is heated at-300 C. for several hours to several ten hours. In the above reaction,an acid catalyst such as boric acid may be used if necessary, wherebythe reaction time can be shortened in some cases.

(3) CATALYTIC DEHYDRATION METHOD This method is carried out in thefollowing manner:

The aforesaid fatty acid and amine are dissolved in a suitable solvent.To this solution is added such a dehydrating agent as sulfuric acid,p-phenolsulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acidchloride, or an anion or cation exchange resin (e.g. IRA-400, IR-50,IR-l20, or Amberlyst 15, 21, 26 or 27). Subsequently, the solution isheated using a water-separator to remove water formed. Thereafter, thesolvent is removed and the resultant is purified, whereby a desiredproduct can be obtained in a markedly high yield and in a simple manner.Alternatively, the object can be achieved by merely heating said acidand amine together with a dehydrating agent in a tertiary organic aminesuch as pyridine, picoline or lutidine as the solvent.

(4) ACID HALIDE METHOD As the fatty acid halide, any of chlorides,bromides and iodides of the aforesaid fatty acids may be used. Of these,the chloride is the most important fatty acid halide and can be preparedaccording to an ordinary procedure.

This method is carried out by dissolving or suspending the benzylaminederivative and an alkaline condensing agent in a suitable solvent, andadding drop by drop fatty acid halides to the said solution or thesuspension.

(5) AMINOLYSIS METHOD This method may be carried out in such a mannerthat a glyceride or lower alkyl ester of fatty acid is mixed with anequimolar amount to about 10 moles of the aforesaid substitutedbenzylbenzylamine derivative and the mixture is reacted at an elevatedtemperature. If necessary, the reaction may be effected in the presenceof an inrt organic solvent. The reaction time is ordinarily 20-200 hoursat below the boiling point of the amine. In order to save the reactiontime, however, the reaction is effected in an autoclave to maintain thereaction temperature at above the boiling point of the amine, or methyl,ethyl or propyl alcohol eliminated during the reaction at atmosphericpressure is removed out of the reaction system. Alternatively, a smallamount of a basic catalyst is added if necessary to the reaction system,or an alcohol or aqueous solution of the catalyst is added to thereactants, whereby the reaction time may be greatly shortened.

(6) MIXED ACID ANHYDRIDE METHOD This method is carried out by reactingat a low temperature the aforesaid substituted benzylbenzyaminederivative with a mixed acid anhydride of chloroformate ester with fattyacid.

It is needless to say that all the amide synthesis methods other thanthose mentioned above can be utilized in the present invention.

According to the researches of the present inventors, it has beenclarified that all the amides obtained by the above methods haveexcellent biological activities which, in animal tests using mice, ratsand rabbits, markedly lower the blood and liver cholesterol thereof,greatly prevent the formation of atheromata on arterial walls, and showno toxicity at all even when administered for a long period of time.These methods are usable in the case of optical active amines.

Toxicities and biological effects of the present amide derivatives areexplained below.

A food high in cholesterol content is given to 10 mice per group. At thesame time, 0.05% of each of the present amide derivatives isadministered to the mice in admixture with said food. When the amountsof serum and liver cholesterol of the mice are measured after 10 days,it is understood that the mice have been greatly lowered in cholesterol.Of many cases tested, several typical cases are shown in the followingtable:

TABLE 1 Serum Liver cholesterol cholesterol (mg. percent) (mg/100 g.)

Control (no substance added) 394 2, 840 Llnoleic acid 361 3, 225

C1rH2uCONH-(]3E[-CH: 208 629 01111.10 ONE-(EEG 224 444 CH: i I CH3d-CuHarC o NH(]711 230 500 CH2 l CH3 l-CnHai C ONE-(13H 200 423 CH: I OHCHHaCQNHoH-Q-cm 255 731 lso-Cr1HaaCONH-(|3H 231 509 TABLE 1-C0ntinuedSerum cholesterol (mg. percent) Liver cholesterol (mg/100 g.)

CHaO-O O CH;

Sardine 011-0 ONHSJH-Q-OzHr OCH Procedures for preparing the presentamide derivatives are illustrated below with reference to examples.

EXAMPLE 1 To a solution of 4 g. of a-(p-methoxyphenyl)-B-phenylethylamine and 2.7 g. of triethylamine in 100 ml. of dry ether wasadded drop by drop a solution of 5.8 g. of linoleic acid chloride in ml.of dry ether under stirring over a period of 1.5 hours at 20 C.

The mixed solution was stirred at said temperature for 2 hours and wasthen allowed to stand overnight at room temperature. Subsequently, theether solution was refluxed for about 2 hours.

After completion of the reaction, the ether solution was washed with a5% hydrochloric acid, water, a 5% sodium carbonate solution and water,in this order, and was then dried with anhydrous sodium sulfate.Thereafter, ether was removed by distillation to obtain 8 g. of N-[a-(p-methoxyphenyl)-fl-phenylethyl]-linoleamide in the form of colorlesspaste.

Elementary analysis.Calculated (percent): C, 80.92; H, 9.69; N,. 2.86.Found (percent): C, 81.05; H, 10.05; N, 3.06.

EXAMPLE 2 Subsequently, the same operations as in Example 1 wereeffected to obtain 19 g. ofN-[a-(p-chlorophenyD-p-phenylethyl]-linoleamide in the form of colorlesssemisolid.

Elementary analysis.Calculated (percent): C, 77.78; H, 8.98; N, 2.83;Cl, 7.18. Found (percent): C, 77.91; H, 8.88; N, 2.66; Cl, 6.92.

EXAMPLE 3 To a solution of 4 g. of u-(p-tolyl)-B-phenylethylamine and2.9 g. of triethylamine in ml. of dry ether was added drop by drop asolution of 6.3 g. of linoleic acid chloride in 20 ml. of dry etherunder stirring over a period of 2 hours.

Subsequently, the same operations as in Example 1 were effected toobtain 7.3 g. of N-[a-(p-tolyD-fi-phenylethylJ-linoleamide in the formof colorless semisolid.

Elementary analysis.Calculated (percent): C, 83.65; H, 10.01; N, 2.96.Found (percent): C, 84.34; H, 10.10; N, 3.23.

EXAMPLE 4 To a mixture of 1.1 g. of triethylamine, 50 ml. of ether and 4g. of a-phenyl-B-(p-methoxyphenyl)-ethylamine was added drop by drop 3.3g. of linoleic acid chloride at room temperature over a period of 1hour. Thereafter, the mixture was stirred for 2 hours and allowed tostand overnight, and then refluxed for 1 hour. The reaction mixture wasextracted with ether and the ether layer was washed with a 5%hydrochloric acid, a 5% sodium hydroxide solution and water, in thisorder, and was then dried.

Subsequently, the ether was removed by distillation to obtain desiredN-[a-phenyl-fl-(p-methoxyphenyl)-ethyl]-linoleamide in the form of whitesemisolid.

Elementary analysis.-Calculated (percent): C, 80.93;

10 EXAMPLE 9 To a mixture of 4 g. of a-(p-tolyl)- 3-phenylethylamine,4.2 g. of dicyclohexylcarbodiimide and 50 ml. of toluene was added amixture of 5.3 g. of oleic acid and 50 ml. 33 Found (percent)' 8132 oftoluene. The resulting mixture was allowed to stand overnight at roomtemperature. Subsequently, deposited EXAMPLE 5 precipitates were removedby filtration, and excess dicyclohexylcarbodiimide was decomposed byaddition of a I Q g 9 i d f z ggl g 10 small amount of acetic acid.Thereafter, the toluene layer an 0 1110531: was ea 6 a was treated asusual manner to obtain 7.9 g. of a desired hours while removing waterformed. After completion of the reaction the reaction mixture wasdissolved in ether product m the form of semlsohd' and the ethersolution was washed with alkali acid and Elementary analysis'mcalculated (percent): 8331; H, 10.38; N, 2.94. Found (percent): C,83.52; H, 10.55; water, in th1s order, and then drled and concentratedto N 2 70 obtain 7.1 g. of a desired product in the form of semisolid.EXAMPLE 10 Elementary analysis.--Calculated (percent): C, 83.65; H,10.01; N, 2.96. Found (percent): C, 83.99; H, 10.09; A mixture of 2.4 g-Of -(py ,5-Xylyl)-ethy1- N, 3,20, amine, 2.9 g. of methyl isostearateand 0.3 g. of sodium EXAMPLE 6 methylate was stirred at 190 C. for about10 hours. Subsequently, the reaction mixture was treated according to Amlxture of of 'q i ordinary procedures to obtain 4.2 g. of a desiredproduct amine and 5.8 g. of safflower oil was heated under stirring at180 C for about 70 hours After completion of the m the form of Semlsohd'Elementary analysis.Calculated (percent): C, 83.11; reaction, thereaction mixture was treated in the same H 10 N 2 77 Found ercent) C 83H 11 manner as in Example to obtain 6.9 g. of adesired prod- 2 6 p notin the form of semlsolid. EXAMPLE 11 EXAMPLE 7 To a solution of 14 g. oflinoleic acid and 5,5 g. of tri- A mixture of 7 g. ofa-(p-bromophenyl)-,3-(p,m-dich1 ethylamine in 100 ml. of tetrahydrofuranwas added drop rophenyl)-ethylamine and 5.8 g. of methyl ester of olive30 y p Of ethyl chloroformate Under StiTriIlg all oil was stirred at 190C. for about 80 hours while ex- 10 C. to =--5 C. Thereafter, thestirring was further eluding methanol distilled out of the reactionsystem. continued at -5 C. for 30 minutes, and then a solution Aftercompletion of the reaction, the reaction mixture was of 11 of '(P' Y)-5-P y y in 20 of treated according to ordinary procedure to obtain 7.6g. tetrahydrofuran was added drop by drop under stirring at of a desiredproduct in the form of semisolid. 5 C. Thereafter, the temperature wasgradually elevated under stirring, and the mixture was stirred at 40 C.EXAMPLE 8 for additional 30 minutes. Subsequently, the tetrahydro- Amixture of 2.3 g. of a-phenyl-B-(2,5-xylyl)-ethylfuran was removed bydistillation and the residue was amine, 2.8 g. of isostearic acid and0.2 g. of p-toluenesuldissolved in ether. The ether solution was treatedas usual fonic acid was boiled for 12 hours in 100 ml. of xylene, 4Omann r t Obtain 21-5 g- Of White semisolid. using a water-separator. Thereaction mixture was treated El mentary analysis.Calculated (percent):C, 84.02; as usual manner to obtain 4.5 g. of white semisolid. H, 9.62;N, 3.39. Found (percent): C, 84.31; H, 9.77;

Elementary analysis.-Calculated (percent): C, 83.03; N, 3.20. H, 10.86;N, 2.85. Found (percent): C, 83.22; H, 10.91; Other preparation examplesof the present amide deriv- N, 2.70. atives are tabulated below.

Analysis, percent Calculated Found Physical Example Compound obtainedproperty 0 H N Halogen C H N Halogen 12 Semiso1id 83.70 10.14 2. 8783.48 10.18 3. 07

C11H3.o0N11-t :H-on,

13 Semiso1id-. 77.76 8.99 2.83 7.17 78.33 8.81 2.20 6.84

O Ha1CONH(l3HOHz-Cl Example Compound obtained 011E310 ONH(l)HCH2OHa17Ha1CONH(|JHCH;-

19 f i C19H31CONH?HOH3 015E310 ONm m-CHZ-Q-CZH,

1 01111310 ONHCH-OHz- Ex. Compound obtained 22.--- Linseed oilconuon-om-Q Analysis, percent Calculated Found Physical property 0 H NHalogen C H N Halogen semisolid--- 83.65 10.01 2 96 83. 94 10. 11 3.03

semisolid-.. 83.65 10. 01 2.96 83.90 10.90 3. 17

Semlsolld--. 84.45 9.52 2. 81 84. 9. 67 3. 01

semisolid... 82.88 10.65 3.02 83.03 10.83 3. 14

semisolid-.- 82.96 10.76 2.93 83. 15 10.76 2.77

' Physical 52523:; Ex. Compound obtained property Semi- Rape oilGQNHCH-Cm-QCm Seml- I solld.

Physical physical Ex. Compound obtained properties Ex. Compound obtainedproperties 24.-.- Safiflower oil CNHCHGH2 CH Semi- 29.-.- Flatfish oilCONHCH-CHz-Q Semisolid. 5 solid.

30. Whale oil GONHCH-CH2- -F Semi- 25- Corn 011 CONHCH-CH: 0 0211Semisolid,

l solid. I

31--.. Sesame oil CONHCHCHn-C2H semlil-d S0 26---- Cuttlefish oilcoNHoH-cm-om Semll solid. Q Q OCHS 32.... God oil 00N110H-0Hz-0fl8 Semi-27.-. Mackerel oll CONHCH-CHr- Semisolid.

| solid. 30

| CH F 33-.-. Soybean oil CONH(|JH- Semli -d S01 2s Sardine oilCONHCHCHz-CzHn Semi- 0112 1 solid. I

| l 0 CH CH3 Analysis, percent Calculated Found Example Compoundobtained Physical property 0 H N C H N 34 0 H HD 1.5250 83. 77 10. 26 2.79 84. 08 10. 38 2. 81

0 E310 ONHCHCE CH. Q

0.111510 QNHQE-Qo-Om l CH C112- 36 M.P., -51 O 83. 67 10. 00 2. 96 83.59 9. 86 2. 86

(31711310 ONHCH- l CH3 37 an+18.0, MR, 83. 67 10. 00 2. 96 83. 10. 23 2.88

(+) 01 11 10 ONHCH- 80-82" C.

Analysis, percent Calculated Found Example Compound obtained Physicalproperty H N C H N 38 urn-17.8, M.P., S3. 67 10. 00 2. 96 83. 77 9. 943. 06

() 01111310 ONHTH- s1-s3 o.

39 Semisolid 84. 02 9. 62 2. 97 83. 88 9. 49 3. 13

'YC 1H29C ONHTH- What we claim is:

1. An amide derivative represented by the formula,

CHPQ

wherein R represents a C C alkyl or alkenyl group and R R R and Rrepresent individually a hydrogen atom, a lower alkyl group, a loweralkoxy group or a halogen atom, but cannot be hydrogen atoms at the sametime.

3. An amide derivative represented by the formula,

wherein R represents a C -C alkyl or alkenyl group which may besubstituted by a hydroxyl, R is a lower alkyl group, a lower alkoxygroup or a halogen atom and R R and R represent individually a hydrogenatom, a lower alkyl group, a lower alkoxy group or a hydrogen atom.

4. An amide derivative represented by the formula,

wherein R represents a C -C alkyl or alkenyl group which may besubstituted by a hydroxyl, R is a lower alkyl group, a. lower alkoxygroup or a halogen atom and R R and R represent individually a hydrogenatom, a lower alkyl group, a lower alkoxy group or a halogen atom.

5. N [0c (p-methoxyphenyl)-fi-phenylethyl]-linoleamide.

6. N- oc- (p-chlorophenyl -fi-phenylethyl] -linoleamide.

7. N- oc- (p-tolyl -B-phenylethyl] -linoleamide.

8. N [a phenyl-fi-(p-methoxyphenyl)-ethyl]-lino1eamide.

9. a-(p-ethylphenyl)-fi-phenylethylamide of safllower oil fatty acid.

10. a (p-bromophenyD-B-(p,m-dichlorophenyl)-ethylamide of olive oilfatty acid.

11. N- [a-phenyl-B- 2,5 -xylyl) -ethyl] -isostearamide.

12. N- oc- (p-tolyl -[3-phenylethyl] -oleamide.

13. N- a- (p-tolyl -B- 2,5 -xylyl -ethyl -isoste aramide.

14. N-[oc (2,5 dimethylphenyl)-B-phenylethyl]-linoleamide.

15. N [a phenyl-fl-(p-chlorophenyl)ethyl]-linoleamide.

16. N [a (p-toly1)-,6-(p-methoxyphenyD-ethyl]-linoleamide.

17. N-[a-(p-tolyl)-p-(p-tolyl)-ethyl]-1inoleamide.

18. N- u-phenyl-fl- (p-tolyl -ethy1] -1inoleamide.

19. N- (d)-a- (p-tolyl)-B-pheny1ethyl] -linoleamide.

20. N- (l -a- (p-tolyl) -B-phenylethyl] -1inoleamide.

21. N- [a- (p-tolyl -B-phenylethyl -arachidonamide.

22. N [a phenyl-B-(p-ethylphenyl)-ethyl]-palmitamide.

23. N- [a- (p-tolyl) -/8-pheny1ethyl] -isostearamide.

24. cc(4,5 dimethoxyphenyl)-fi-phenylethylamide of linseed oil fattyacid.

25. a-(p-tolyl)-B-(p-tolyl)-ethylamide of rape oil fatty acid.

26. u-(p-tolyl)-fl-(p-tolyl)-ethy1arnide of satfiower oil fatty acid.

27. a-phenyl-fi-(p-ethoxyphenyl)-ethy1arnide of corn Oil fatty acid.

28.apheny1-,8-(p-to1y1)-ethy1arnide of cuttlefish oil fatty acid.

29. a-(p-fluorophenyl)-fl-pheny1ethy1amide of mackerel oil fatty acid.

30. a (p ethoxyphenyl)-[3-(p-ethy1pheny1)-ethy1- amide of sardine oilfatty acid.

31. u-(p-ethoxyphenyl)-fi-pheny1ethylamide of flatfish oil fatty acid.

32. a-pheny1-5-(p-fluorophenyl)-ethy1amide of whale oil fatty acid.

33. a (p methoxyphenyl)-[3-(p-ethylpheny1)-ethy1- amide of sesame oilfatty acid.

34. a-(p-tolyl)-,B-(p-toly1)-ethy1amide of cod oil fatty acid.

35. a-phenyl-fi-(p-tolyl)-ethylamide of soybean oil fatty acid.

36. N [a (p-isopropylphenyl)-,B-pheny1ethyl]-1inoleamide.

37. N [a (p-t-butylphenyl)-fl-pheny1ethy1]-linoleamide.

References Cited UNITED STATES PATENTS 2,503,285 4/1950 McPhee 260570.52,506,588 5/1950 Goodson et a1 260--570.5 3,193,458 7/1965 Shapiro eta1. 424-320 3,253,006 5/1966 Davis 260-404 FOREIGN PATENTS 1,051,28612/1966 Great Britain 260-404 1,057,742 2/1967 Great Britain 2604041,123,004 8/1968 Great Britain 260404 20 LEWIS GOTTS, Primary ExaminerG. HOLLRAH, Assistant Examiner US. Cl. X.R.

